The use of aldehyde dehydrogenase (ALDH) inhibitors is one pharmacotherapeutic approach which has been employed for the treatment of alcohol (ethanol) abuse and alcoholism. Examples of these types of compounds presently used clinically are disulfiram (tetraethylthiuram disulfide) (Antabuse.RTM.), and carbimide (citrated calcium carbimide, cyanamide (Temposil.RTM.)). Disulfiram is used through-out the world, whereas calcium carbimide has not been approved by the FDA for use in the United States.
The rationale for the use of ALDH inhibitors such as disulfiram for the treatment of alcoholism is that they block the metabolism of ethanol. Thus, after ethanol ingestion, inhibitors of liver mitochondrial low Km ALDH cause an increase in the formation of acetaldehyde. Clinically, this leads to tachycardia, hypotension, nausea, and other adverse symptoms that are referred to as the disulfiram-ethanol reaction (DER). Although disulfiram is widely used in the treatment of alcoholism, its use is not without controversy. A number of reports have questioned disulfiram's toxicity and its ability to produce a DER that is effective to deter ethanol ingestion.
Endogenous opioid peptides are involved in the mediation or modulation of a variety of mammalian physiological processes, many of which are mimicked by opiates or other non-endogenous opioid ligands. Some of the effects that have been investigated are analgesia, tolerance and dependence, appetite, renal function, gastrointestinal motility, gastric secretion, learning and memory, mental illness, epileptic seizures and other neurological disorders, cardiovascular responses, and respiratory depression.
The fact that the effects of endogenous and exogenous opioids are mediated by at least three different types [mu (.mu.), delta (.delta.), kappa (.kappa.)] of opioid receptors raises the possibility that highly selective exogenous opioid agonist or antagonist ligands might have therapeutic applications. See W. R. Martin, Pharmacol. Rev., 35, 283 (1983). Thus, if a ligand acts at a single opioid receptor type or subtype, the potential side effects mediated through other opioid receptor types can be minimized or eliminated.
The prototypical opioid antagonists, naloxone and naltrexone, are used primarily as pharmacologic research tools and for the reversal of toxic effects of opioids in case of overdose. Since these antagonists act at multiple opioid receptors, their application in other therapeutic areas or as pharmacologic tools appear to be limited. However, naltrexone recently was reported to reduce the incidence of relapse in recovering alcoholics by J. R. Volpicelli et al., Opioids, Bulimia and Alcohol Abuse and Alcoholism, L. D. Reid, ed., Springer-Verlag (1990) at pages 195-214. Naloxone has been reported to suppress ethanol but not water intake in a rat model of alcoholism. J. C. Froehlich et al., Pharm. Biochem. Behav., 35, 385 (1990).
Some progress has been made in the development of highly selective opioid antagonists. For example, Portoghese et al. (U.S. Pat. No. 4,816,586) disclose certain opiate analogs which possess high selectivity and potency at delta receptors. Minimal involvement was observed at mu and kappa opioid receptors. One of the highly selective analogs disclosed in U.S. Pat. No. 4,816,586 has been named "naltrindole" or "NTI," and has the formula: ##STR2##
See P. S. Portoghese et al., J. Med. Chem., 31, 281 (1988).
It has recently been reported that suppression of ethanol ingestion may be mediated by the delta opioid receptor type. For example, the established .delta. antagonist, N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI 174864), strongly inhibits ethanol drinking, but has a very short duration of action, which may limit its clinical utility. See J. C. Froehlich et al., Psychopharmacol., 103, 467 (1991). Using NTI as an antagonist, M. Sofuoglu et al., J. Pharmacol. Exp. Ther., 257, 676 (1991) determined that the antinociceptive activity of two delta receptor agonist enkephalin analogs, DSLET and DPDPE, may be mediated by two discrete delta opioid receptor subtypes.
Therefore, a continuing need exists for compounds which are .delta. opioid receptor-selective. Delta opioid receptor antagonists are needed to develop pharmacological approaches to the treatment of alcohol dependence. More specifically, a need exists for an effective method to deter ethanol ingestion by humans using specific and potent .delta. opioid receptor antagonists, which have a duration of action and ability to access the central nervous system which are superior to the peptide-based .delta. receptor antagonists.